A wide variety of cutaneous disorders may affect immunocompromised pediatric patients. Children can be immunocompromised due to an underlying malignancy, immunodeficiency, or secondary to immunosuppressive therapy. Chronic immunosuppressive therapies may be administered for numerous reasons including solid organ transplantation and chronic conditions. In addition, immunosuppression may result from chemotherapeutic treatment regimens for malignancies or conditioning regimens in preparation for bone marrow or stem cell transplantation. The cutaneous disorders associated with immunosuppression range in severity. Even the most banal skin lesions in immunocompromised children can herald life-threatening conditions. Skin biopsies can thus be useful tools in immunosuppressed patients with skin lesions to aid in diagnosis.¹ Skin lesions are most frequently a consequence of drug side effects or infection caused by immunosuppression.^2,3 Skin disorders affecting immunocompromised patients may occur acutely during high levels of immunosuppression (such as in transplant patients during the early post-transplant period or during periods of acute rejection), while other skin eruptions may be secondary to exposure to various medications. Table 66-1 displays a range of cutaneous lesions seen in immunocompromised patients.

Graft-versus-host disease (GVHD), an important disorder with various cutaneous manifestations, is discussed in Chapter 134.

Infections with common and unusual organisms are a complication of immunosuppression. Extensive involvement caused by relatively minor but still problematic skin infections such as tinea corporis, pityriasis (tinea) versicolor, or viral warts is a consequence of long-term immunosuppression.^2-4 The most worrisome complication of chronic immunosuppression is the increased risk of life-threatening skin infections that may be associated with significant morbidity The clinical presentation of cutaneous infections caused by a variety of different pathogens is often similar. Prompt evaluation and treatment of these life-threatening infections can reduce morbidity and mortality. Cutaneous lesions suspicious for an infectious process should be biopsied and sent for routine histology, special stains, and tissue culture, as superficial skin cultures are often not sufficient to establish a diagnosis.

BACTERIAL INFECTIONS

Bacterial infections such as impetigo, folliculitis, and cellulitis may arise in immunocompromised patients. Moreover, skin infection may herald or coincide with systemic infection with a variety of pathogens. Common pathogens such as Staphylococcus aureus and group A streptococci may be causative agents, but less common pathogens, including gram-negative organisms, may also cause skin disease. Ecthyma gangrenosum is a manifestation of Pseudomonal sepsis that can occur in debilitated and immunocompromised hosts. It begins as an erythematous to purpuric patch that evolves into a hemorrhagic bulla, which progresses to a necrotic ulcer or eschar. This life-threatening infection must be recognized early and treated promptly (see Chapter 62). Disseminated nocardiosis from a pulmonary source may occur in severely immunocompromised individuals presenting with nonspecific skin lesions (papules and nodules).^5,6

FUNGAL INFECTIONS

Infections caused by yeasts and molds typically occur when immunosuppression is greatest. In transplant patients, this is often during the first few months after transplantation or when increased immunosuppression is instituted to treat rejection.^7-9 The majority of children with cutaneous mold infections have hematologic malignancies, most commonly leukemia or lymphoma. All 18 children in one series were immunocompromised, and most children were severely neutropenic at the time infection was diagnosed.¹⁰ Skin lesions may represent primary infection with the potential for dissemination to other organs or metastatic disease from pre-existing systemic organ involvement. Isolated or localized lesions may quickly lead to disseminated infection, which harbors a poor prognosis. Systemic disease caused by a variety of pathogens, including Aspergillus, Fusarium, Alternaria, Paecilomyces, and the mucormycetes may present early as an erythematous patch or nodule that in some cases evolves into an ulcerated, necrotic plaque or multiple erythematous pustules or nodules (Figure 66-1).^11-14 Skin lesions of aspergillosis often present at sites of intravenous catheterization or occlusion by tape or wound dressings.¹²

Candida species may cause localized skin disease such as intertrigo and folliculitis or Candida sepsis. Candida sepsis may present as erythematous papules or papulopustules, often on the trunk and extremities. Disseminated cryptococcosis presents as nonspecific papules or areas of cellulitis.^7,15 Dermatophyte fungus (Trichophyton species) may cause widespread superficial skin infections, including tinea capitis, tinea pedis, and tinea corporis. These common infections are usually not life threatening but may serve as a portal of entry for other pathogens that cause systemic disease.

In addition to the above fungi, Trichosporon species—which most commonly cause innocuous superficial infections of the hair in immunocompetent hosts—are a known cause of systemic illness in immunocompromised patients, especially in those with hematologic malignancy.¹⁶ A high index of suspicion is paramount in life-threatening, disseminated infections with Trichosporon spp., as they may present as non-specific erythematous eruptions.

MYCOBACTERIAL INFECTIONS AND PARASITES

Nontuberculous mycobacteria (Mycobacterium kansasii, M. avium-intracellulare, M. fortuitum, M. marinum, M. abscessus, and others) may present as subcutaneous nodules and abscesses.^17,18 In addition to these pathogens, parasites such as Leishmania are reported to cause visceral disease and subsequent cutaneous infection in young adults following organ transplantation.¹⁹

VIRAL INFECTIONS

The risk for herpesvirus infections (herpes simplex virus, varicella zoster virus, cytomegalovirus) is increased in patients with decreased immunity. For example, cutaneous viral infections caused by herpes simplex viruses 1 and 2 may be more extensive in transplant recipients and cause lesions that mimic pressure ulcers. Reactivation of varicella-zoster virus commonly leads to herpes zoster in immunocompromised hosts. Early initiation of antiviral therapy is important to decrease the incidence of cutaneous and visceral dissemination that can result in life-threatening complications.²⁰ The presentation of zoster may not be limited strictly to a dermatomal distribution. Disseminated varicella-zoster virus infection is recognized when more than 20 skin lesions are present outside the affected dermatome or the immediately adjacent dermatome(s). Cytomegalovirus, a common cause of systemic infection in solid organ transplant recipients, may also cause a wide variety of skin lesions, including periorificial ulcers, nodules, and plaques and a diffuse exanthem.²¹ An increased incidence of herpesvirus infections has been reported in patients taking immunosuppressive medications, especially mycophenolate mofetil, an agent used primarily for prevention of solid organ transplant rejection, as well as off-label use for a variety of inflammatory dermatologic conditions.²²

Viral warts caused by human papillomavirus (HPV) are common and troublesome to immunosuppressed patients. They are often numerous, painful, and unsightly. Moreover, the association of HPV with squamous cell carcinoma is troubling. Verruca vulgaris is especially common in organ transplant recipients and is reported to occur in 13% to 54% of patients.^2,3 Warts can occur anywhere on the skin or mucosal surfaces. There is often a history of common viral warts before transplantation, and the prevalence increases over time. Spontaneous regression is uncommon, and treatment is often challenging. Destructive treatments are often used, but these are painful and may be complicated by poor wound healing or infection. Imiquimod, a topical immunomodulator, has been used in adult transplant recipients;^23,24 however, its safety and efficacy remain to be determined in pediatric organ transplant recipients. Sinecatechins (Veregen) ointment is a newer agent derived from green tea leaves and is FDA-approved for genital warts. Sinecatechins is thought to have antioxidative properties, but its safety and efficacy in immunocompromised patients has not been studied.²⁵

In immunosuppressed children, molluscum contagiosum can present atypically and in large numbers. Vesicular lesions, papules that lack typical umbilication, and giant nodules in some cases with ulceration have been reported.²⁶ Molluscum occurs in 7% of pediatric organ transplant recipients. These lesions arise in the usual locations including the face, trunk, extremities, and especially the folds, but are often multiple and resistant to conventional treatment.²

An increased risk of malignant neoplasms is one of the most concerning consequences of immunosuppression. Chronic immunosuppression causing reduced immune-mediated tumor surveillance is believed to lead to the increased incidence of cancer. An overall three- to fourfold increase in cancer risk is reported.²⁷ Cutaneous cancers (squamous cell, basal cell, and melanoma), post-transplant lymphoproliferative disorder, Kaposi sarcoma, and other sarcomas are commonly reported malignancies.²⁷ Factors increasing the skin cancer incidence in organ transplant recipients, for example, include older patient age, longer duration of immunosuppression, intensity of immunosuppression, ultraviolet light exposure, infection with HPV, and fair skin. Lymphomas, skin and lip carcinomas, sarcomas, and anal and vulvar carcinomas are the most frequently reported malignant neoplasms in pediatric transplant recipients.^28,29 Post-transplant lymphoproliferative disorder may present in the skin as subcutaneous nodules.³⁰ Squamous cell carcinoma is the most common skin cancer in solid organ transplant recipients; there is a 65-fold increase in the overall incidence of squamous cell carcinoma, a 20-fold increase in squamous cell carcinoma of the lip, a 10-fold increase in basal cell carcinoma, and 3- to 4-fold increase in melanoma.²⁷ Squamous cell carcinomas arising in transplant recipients are often multiple, have a younger age of onset than in the general population, and are more aggressive. Pediatric transplant recipients also show increased rates of metastases from skin tumors and increased mortality. In addition to solid organ transplant recipients, patients with hematologic malignancies, bone marrow and stem cell transplant recipients, and patients who received chemotherapy or other therapeutic immunosuppressants have an increased risk of developing skin cancers.³¹ As a consequence of childhood cancer therapy, several factors lead to secondary cutaneous malignancies including disease-associated immunosuppression, chemotherapy-associated immunosuppression, immunosuppression associated with GVHD prophylaxis in bone marrow transplant recipients, and radiation therapy. Data regarding secondary malignancies as part of the Childhood Cancer Survivor Study from the National Cancer Institute, which surveyed more than 14,000 childhood cancer survivors, noted that children who received radiation therapy for childhood cancer were at 6.3 times higher risk for developing non-melanoma skin cancer than those children who did not receive radiation.³² Malignant melanomas also occurred as secondary malignancies in childhood cancer survivors.³²